A fundamental question during assisted ventilation in the ICU is how to synchronize the ventilator rhythm with the patient's breathing effort smoothly and effectively. Dyssynchrony could lead to increased/wasted work of breathing, patient discomfort, increased need for sedation, higher rate of tracheostomy, longer durations of mechanical ventilation and reduced number of ventilator-free days, longer ICU and hospital stay, and lower probabilities of survival and home discharge. Current generation ventilators either dictate the breathing rhythm completely with the use of heavy sedation/muscle paralysis (ventilator-based ventilation) or let the patient trigger the ventilator breath by breath (patient-based ventilation). Neither extreme is optimal. We propose a next generation of ventilatory assist (entrainment-based mechanical ventilation, EMV) that is based on the classical physics theory of mutual entrainment between coupled oscillators, which may provide a cost-effective solution to this clinical problem. This innovative technique is motivated by our recent discovery that the brain circuits controlling breathing are capable of entraining to a ventilator and adaptin to it through learning and memory of the Hering-Breuer inflation reflex. In EMV, the patient's spontaneous respiratory rhythm and the ventilator rhythm are phase-locked to one another on the same tempo, just like two individuals dancing together. Under a previous NIH ARRA Challenge Grant (RC1) award we have implemented a prototype of EMV on a widely used mechanical ventilator (Puritan-Bennett Model 840) and demonstrated the feasibility of this novel technique on a computerized lung simulator. Based on these simulation results, a conditional approval for investigational device exemption has been recently granted by the FDA for initial clinical research of the EMV mode. To transition the base technology from the bench top to the bedside, a multidisciplinary research team comprised of a basic researcher/bioengineer (Dr. Poon, PI), a clinician (Dr. Harris, Co-I), a biostatistician (Dr. Schoenfeld, statistical consultan) and a technology developer (Covidien/Puritan-Bennett) has been formed to address the underlying scientific, engineering, statistical and clinical problems. The goal of this pilot projet is to first establish that the proposed EMV mode is both safe and effective in entraining the patient's breathing rhythm over a short (4-hour) period (Aim 1). This phase I clinical research wil allow us to fine-tune the parameters of the EMV mode in order to further minimize risks and maximize the effectiveness of the EMV mode in improving patient-ventilator synchrony over a long period. The second phase (Aim 2) is to establish that the EMV mode is safe and feasible in providing improved synchrony in ARDS patients when used over a patient's entire ventilation weaning period. The proposed phase I/phase II research are both necessary and sufficient for securing FDA approval of a full-scale phase III multicenter trial to be conducted in the future in order to test whether improved patient-ventilator synchrony with the EMV mode may lead to materially beneficial clinical outcomes during ventilator weaning.